US20140024638A1 - Treatment of cognitive dysfunction in schizophrenia - Google Patents

Treatment of cognitive dysfunction in schizophrenia Download PDF

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US20140024638A1
US20140024638A1 US13/980,091 US201213980091A US2014024638A1 US 20140024638 A1 US20140024638 A1 US 20140024638A1 US 201213980091 A US201213980091 A US 201213980091A US 2014024638 A1 US2014024638 A1 US 2014024638A1
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azabicyclo
pyridinyl
schizophrenia
methyl
benzofuran
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Merouane Bencherif
Geoffrey C. Dunbar
David A. Hosford
Gregory J. Gatto
Terry Hauser
Kristen G. Jordan
Anthony Carl Segreti
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Catalyst Biosciences Inc
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Targacept Inc
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Assigned to TARGACEPT, INC. reassignment TARGACEPT, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: HOSFORD, DAVID A., SEGRETI, Anthony Carl, DUNBAR, GEOFFREY CHARLES, HAUSER, TERRY, JORDAN, KRISTEN G., BENCHERIF, MEROUANE, GATTO, GREGORY J.
Publication of US20140024638A1 publication Critical patent/US20140024638A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention relates to methods and uses for (2S,3R)—N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof.
  • Schizophrenia is a chronic, severe, and disabling form of psychosis.
  • symptoms such as delusions, hallucinations, the inability to disregard familiar stimuli (sometimes referred to as sensory gating), disorganized speech, grossly disorganized or catatonic behavior and prolonged loss of emotion, feeling, volition or drive, schizophrenia is often marked by impairment in cognitive functions, such as executive function, attention, vigilance, memory and reasoning.
  • cognitive impairments play a primary role in the inability of schizophrenic patients to function normally.
  • one measure of clinical efficacy for cognitive dysfunction in schizophrenia includes the Schizophrenia Cognitive Test Battery.
  • Schizophrenia can be divided into three major phases: the prodromal state, an active phase, and a residual phase. These phases tend to occur in sequence and appear in cycles throughout the course of the illness.
  • the active phase of the illness psychotic symptoms such as delusions, odd behavior and hallucinations are prominent and are often accompanied by strong affect such as distress, anxiety, depression, and fear. If untreated, the active phase may resolve spontaneously or may continue indefinitely. With appropriate treatment (primarily medication) the active phase is usually able to be brought under control. It is during the active phase that most individuals present for treatment, whether it is their first presentation or an exacerbation of their symptoms.
  • schizophrenia's active phase people may experience delusions, hallucinations, marked distortions in thinking and disturbances in behavior and feelings. This phase most often appears after a prodromal period. On occasion, these symptoms can appear suddenly.
  • the active phase of the illness is usually followed by a residual phase.
  • the residual phase is similar to the prodromal phase although during the residual phase blunted affect and impairment in role functioning are more common. While psychotic symptoms may persist into the residual phase, the psychotic symptoms are less likely to be accompanied by such strong affect as experienced during the active phase. There is great variation in the severity of the residual phase from one person to the next. Some individuals will function extremely well while others may be considerably more impaired. After an active phase, people may be listless, have trouble concentrating and be withdrawn. The symptoms in this phase are similar to those outlined under the prodromal phase. If there have been no symptoms before the first episode, few or no symptoms may be experienced afterward.
  • the most common course of the disorder generally involves numerous active phases of illness with residual phases of impairment between episodes.
  • the extent of residual impairment often increases between episodes during the initial years of the disorder although may possibly become less severe during the later phases of the illness.
  • the invention relates to the treatment of cognitive dysfunction in schizophrenia by administering (2S,3R)—N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof to a patient in need thereof.
  • the invention relates to treatment of cognitive dysfunction in schizophrenia by improving executive function.
  • the invention relates to treatment of cognitive dysfunction in schizophrenia by improving memory.
  • the invention relates to treatment of cognitive dysfunction in schizophrenia by improving attention.
  • the invention relates to treatment of negative symptoms of schizophrenia by administering (2S,3R)—N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof to a patient in need thereof.
  • the invention relates to the treatment of residual phase schizophrenia.
  • Protocol Various terms used herein, not otherwise defined, may be defined with reference to the Protocol.
  • FIG. 2 illustrates sensitivity of the primary outcome measures from the CogState schizophrenia battery to cognitive impairment in patients with chronic schizophrenia who were receiving antipsychotic medication in three different geographical areas. The nature and magnitude of impairment in the different cognitive domains was consistent across the three cultural groups.
  • (2S,3R)—N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof is a selective alpha7 NNR agonist.
  • (2S,3R)—N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof had efficacy in preclinical models of memory and was generally well tolerated in phase 1 trials in healthy volunteers, who demonstrated a robust improvement in attention when 6.7 mg (2S,3R)—N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof was administered.
  • (2S,3R)—N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof met the protocol criteria for a positive result on the primary efficacy outcome measure, the Groton Maze Learning Task (GMLT) of the CogState Schizophrenia Battery (CogState, New Haven, Conn.), and was well tolerated.
  • the trial is Study Number PRO-05619-CRD-001, incorporated herein below.
  • (2S,3R)—N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof exhibited a favorable tolerability profile in the trial, and there was no clinically significant difference between the (2S,3R)—N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof and placebo dose groups in discontinuations due to adverse events.
  • the MATRICS initiative has highlighted the potential for small molecules that target the alpha7 NNR receptor in the treatment for cognitive dysfunction in schizophrenia. That potential was supported by preclinical models of schizophrenia in which the alpha 7 NNR agonist, (2S,3R)—N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof, was effective; and by early clinical studies in which a variety of other alpha7 NNR agonists were effective against surrogate markers (Olincy et al., 2006; EnVivo Pharmaceuticals, 2009) and measured features of schizophrenia (Freedman et al., 2008).
  • the compound of the present invention is (2S,3R)—N(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide, represented as Compound A below, or a pharmaceutically acceptable salt forms of Compound A.
  • Compound A is a highly selective, full agonist at the ⁇ 7 NNR receptor with a remarkably low EC 50 (for activation) value and a good separation between EC 50 and the IC 50 (for residual inhibition), providing functional agonism over a broad range of therapeutically useful concentrations.
  • the scalable synthesis utilizes both the dynamic resolution of a racemizable ketone (2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octan-3-one) and the stereoselective reduction of the (R)- ⁇ -methylbenzylamine imine derivative (reductive amination) of the resolved ketone.
  • the synthetic sequences reported herein are readily scalable and avoid chromatographic purifications.
  • (2S,3R)—N-(2-((3-Pyridinyl)methyl-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide as a free base is an amorphous powder with very limited water solubility.
  • the free base will react with both inorganic and organic acids to make certain acid addition salts that have physical and chemical properties that are advantageous for the preparation of pharmaceutical compositions, including but not limited to crystallinity, water solubility, and stability.
  • the stoichiometry of the salts of the present invention can vary.
  • the salts can have crystal structures that occlude solvents that are present during salt formation.
  • the salts can occur as hydrates and other solvates of varying stoichiometry of solvent relative to the (2S,3R)—N-(2-((3-pyridinyl)methyl-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide.
  • the method for preparing the salt forms can vary.
  • the preparation of (2S,3R)—N-(2-((3-pyridinyl)methyl-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide salt forms generally involves: (i) mixing the free base or a solution of the free base, namely (2S,3R)—N-(2-((3-pyridinyl)methyl-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide in a suitable solvent with an acid neat, or as a solution of an acids in a suitable solvent; (iia) cooling the resulting salt solution, if necessary to cause precipitation; or (iib) adding a suitable anti-solvent to cause precipitation; or (iic) evaporating the first solvent and adding a new solvent and repeating either steps (iia) or step (iib); and (iii) filtering and collecting the resulting salt.
  • solvents that can be used to prepare or recrystallize the salt forms include, without limitation, ethanol, methanol, isopropyl alcohol, acetone, ethyl acetate, and acetonitrile.
  • Suitable pharmaceutically acceptable salts include inorganic acid addition salts such as chloride, bromide, sulfate, phosphate, and nitrate; organic acid addition salts such as acetate, galactarate, propionate, succinate, lactate, glycolate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, p-toluenesulfonate, and ascorbate; and salts with amino acids such as aspartate and glutamate.
  • the salts may be in some cases hydrates or ethanol solvates. Representative salts are provided as described in U.S. Pat. Nos.
  • Salt screening for the free base (2S,3R)—N-(2-((3-pyridinyl)methyl-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide revealed that, while many salts of pharmaceutically acceptable acids could be formed, only a few of these salts had acceptable properties for commercial manufacture. The ability to predict the characteristics exemplified by a commercially viable salt, therefore, does not exist.
  • Acids that provided salts that were crystalline, namely salts that demonstrate some degree of crystallinity, dependent upon the method by which they are prepared, include hydrochloric acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, galactaric (mucic) acid, D-mandelic acid, D-tartaric acid, methanesulfonic acid, R- and S-10-camphorsulfonic acids, maleic acid, ketoglutaric acid and hippuric acid.
  • the hydrochloric acid, phosphoric acid, maleic acid and p-toluenesulfonic acid salts each exhibited additional desirable properties, including high melting points, good water solubility, and low hygroscopicity.
  • compositions of the present invention include the salts described herein, in the pure state or in the form of a composition in which the compounds are combined with any other pharmaceutically compatible product, which can be inert or physiologically active.
  • the resulting pharmaceutical compositions can be used to prevent a condition or disorder in a subject susceptible to such a condition or disorder, and/or to treat a subject suffering from the condition or disorder.
  • the pharmaceutical compositions described herein include the compound of the present invention and/or pharmaceutically acceptable salts thereof.
  • compositions are preferably administered orally (e.g., in liquid form within a solvent such as an aqueous or non-aqueous liquid, or within a solid carrier).
  • Preferred compositions for oral administration include pills, tablets, capsules, caplets, syrups, and solutions, including hard gelatin capsules and time-release capsules.
  • Standard excipients include binders, fillers, colorants, solubilizers, and the like.
  • Compositions can be formulated in unit dose form, or in multiple or subunit doses.
  • Preferred compositions are in liquid or semisolid form.
  • Compositions including a liquid pharmaceutically inert carrier such as water or other pharmaceutically compatible liquids or semisolids can be used. The use of such liquids and semisolids is well known to those of skill in the art.
  • compositions can also be administered via injection, i.e., intravenously, intramuscularly, subcutaneously, intraperitoneally, intraarterially, intrathecally; and intracerebroventricularly.
  • Intravenous administration is the preferred method of injection.
  • Suitable carriers for injection are well known to those of skill in the art and include 5% dextrose solutions, saline, and phosphate-buffered saline.
  • the drug product can also be administered as an infusion or injection (e.g., as a suspension or as an emulsion in a pharmaceutically acceptable liquid or mixture of liquids).
  • the formulations can also be administered using other means, for example, rectal administration.
  • Formulations useful for rectal administration such as suppositories, are well known to those of skill in the art.
  • the drug product can also be administered by inhalation (e.g., in the form of an aerosol either nasally or using delivery articles of the type set forth in U.S. Pat. No. 4,922,901 to Brooks et al., the disclosure of which is incorporated herein in its entirety); topically (e.g., in lotion form); transdermally (e.g., using a transdermal patch) or iontophoretically; or by sublingual or buccal administration.
  • inhalation e.g., in the form of an aerosol either nasally or using delivery articles of the type set forth in U.S. Pat. No. 4,922,901 to Brooks et al., the disclosure of which is incorporated herein in its entirety
  • topically e.g., in lotion form
  • transdermally e
  • compositions used and the particular subject receiving the treatment can contain a liquid carrier that can be oily, aqueous, emulsified or contain certain solvents suitable to the mode of administration.
  • compositions can be administered intermittently or at a gradual, continuous, constant or controlled rate to a warm-blooded animal (e.g., a mammal such as a mouse, rat, cat, rabbit, dog, pig, cow, or monkey), but advantageously are administered to a human being.
  • a warm-blooded animal e.g., a mammal such as a mouse, rat, cat, rabbit, dog, pig, cow, or monkey
  • time of day and the number of times per day that the pharmaceutical formulation is administered can vary.
  • the compound of the present invention may be administered in combination with other therapeutic compounds or alternative, supplemental therapies.
  • One aspect of the present invention includes a combination of (2S,3R)—N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof, with one or more antipsychotic medications, anti-depressants, or mood stabilizers.
  • One aspect of the present invention includes a combination of (2S,3R)—N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof, with one or more of: Stelazine (Trifluoperazine), Flupenthixol (Fluanxol), Loxapine (Loxapac, Loxitane), Perphenazine (Etrafon, Trilafon), Chlorpromazine (Thorazine), Haldol (Haloperidol), Prolixin (Fluphenazine Decanoate, Modecate, Permitil), Atypical Medications for Schizophrenia including but not limited to: Aripiprazole (Abilify) Clozaril (clozapine), Geodon (ziprasidone), Risperdal (resperidone), Seroquel (Quetiapine), or Zyprex
  • supplemental therapies can include psychosocial or cognitive therapy, rehabilitation day programs, peer support groups, nutritional supplements, etc.
  • electroconvulsive therapy which has been shown to be safe and effective
  • transcranial magnetic stimulation TMS
  • Another aspect of the present invention includes a combination of (2S,3R)—N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof with one or more supplemental therapy.
  • the compounds of the present invention may be employed alone or in combination with other therapeutic agents.
  • Such a combination of pharmaceutically active agents may be administered together or separately and, when administered separately, administration may occur simultaneously or sequentially, in any order.
  • the amounts of the compounds or agents and the relative timings of administration will be selected in order to achieve the desired therapeutic effect.
  • the administration in combination may be by administration concomitantly in: (1) a unitary pharmaceutical composition including multiple compounds; or (2) separate pharmaceutical compositions each including one of the compounds.
  • the combination may be administered separately in a sequential manner wherein one treatment agent is administered first and the other second or vice versa. Such sequential administration may be close in time or remote in time.
  • the compounds of the present invention may be used in the treatment of a variety of disorders and conditions and, as such, the compounds of the present invention may be used in combination with a variety of other suitable therapeutic agents useful in the treatment or prophylaxis of those disorders or conditions.
  • the appropriate dose of the compound is that amount effective to prevent occurrence of the symptoms of the disorder or to treat some symptoms of the disorder from which the patient suffers.
  • effective amount therapeutic amount or “effective dose” is meant that amount sufficient to elicit the desired pharmacological or therapeutic effects, thus resulting in effective prevention or treatment of the disorder.
  • an effective amount of compound is an amount sufficient to pass across the blood-brain barrier of the subject, to bind to relevant receptor sites in the brain of the subject and to modulate the activity of relevant NNR subtypes (e.g., provide neurotransmitter secretion, thus resulting in effective prevention or treatment of the disorder).
  • An example of prevention of a disorder is manifested by delaying the onset of the symptoms of the disorder.
  • An example of treatment of a disorder is manifested by a decrease in the symptoms associated with the disorder or an amelioration of the recurrence of the symptoms of the disorder.
  • the effective amount is sufficient to obtain the desired result, but insufficient to cause appreciable side effects.
  • the effective dose can vary, depending upon factors such as the condition of the patient, the severity of the symptoms of the disorder, and the manner in which the pharmaceutical composition is administered.
  • the effective dose of typical compounds generally requires administering the compound in an amount sufficient to modulate the activity of relevant NNRs, but the amount should be insufficient to induce effects on skeletal muscles and ganglia to any significant degree.
  • the effective dose of compounds will of course differ from patient to patient, but in general includes amounts starting where CNS effects or other desired therapeutic effects occur but below the amount where muscular effects are observed.
  • the compounds described herein when employed in effective amounts in accordance with the methods described herein, can provide some degree of prevention of the progression of, ameliorate symptoms of, or ameliorate, to some degree, the recurrence of CNS or other disorders.
  • the effective amounts of those compounds are typically below the threshold concentration required to elicit any appreciable side effects, for example those effects relating to skeletal muscle or ganglia.
  • the compounds can be administered in a therapeutic window in which certain CNS and other disorders are treated and certain side effects are avoided.
  • the effective dose of the compounds described herein is sufficient to provide the desired effects upon the disorder but is insufficient (i.e., is not at a high enough level) to provide undesirable side effects.
  • the compounds are administered at a dosage effective for treating the CNS or other disorders but less than, often less than 1 ⁇ 5, and often less than 1/10, the amount required to elicit certain side effects to any significant degree.
  • effective doses are at very low concentrations, where maximal effects are observed to occur, with a minimum of side effects.
  • the effective dose of such compounds generally requires administering the compound in an amount of less than 5 mg/kg of patient weight.
  • the compounds of the present invention are administered in an amount from less than about 1 mg/kg patent weight and usually less than about 100 ⁇ g/kg of patient weight, but frequently between about 10 ⁇ g to less than 100 ⁇ g/kg of patient weight.
  • the foregoing effective doses typically represent that amount administered as a single dose, or as one or more doses administered over a 24-hour period.
  • the effective dose of typical compounds generally requires administering the compound in an amount of at least about 1, at least about 10, and at least about 100 mg/24 hr/patient.
  • the effective dose of typical compounds requires administering the compound which generally does not exceed about 500, often does not exceed about 400, and frequently does not exceed about 300 mg/24 hr/patient.
  • the compositions are advantageously administered at an effective dose such that the concentration of the compound within the plasma of the patient normally does not exceed 150 ng/mL, often does not exceed 50 ng/mL, and frequently does not exceed 20 ng/mL.
  • an effective dose is between about 1 mg and 50 mg in a 24-hour period.
  • intrinsic activity or “efficacy” relates to some measure of biological effectiveness of the binding partner complex.
  • receptor pharmacology the context in which intrinsic activity or efficacy should be defined will depend on the context of the binding partner (e.g., receptor/ligand) complex and the consideration of an activity relevant to a particular biological outcome.
  • intrinsic activity may vary depending on the particular second messenger system involved. See Hoyer, D. and Boddeke, H., Trends Pharmacol. Sci. 14(7): 270-5 (1993), herein incorporated by reference with regard to such teaching.
  • neurotransmitters whose release is mediated by the compounds described herein include, but are not limited to, acetylcholine, dopamine, norepinephrine, serotonin, and glutamate, and the compounds described herein function as modulators at the ⁇ 7 subtype of the CNS NNRs.
  • prevention or “prophylaxis” include any degree of reducing the progression of or delaying the onset of a disease, disorder, or condition.
  • the term includes providing protective effects against a particular disease, disorder, or condition as well as amelioration of the recurrence of the disease, disorder, or condition.
  • the invention provides a method for treating a subject having or at risk of developing or experiencing a recurrence of a NNR or nAChR mediated disorder.
  • the compounds and pharmaceutical compositions of the invention may be used to achieve a beneficial therapeutic or prophylactic effect, for example, in a subject with a CNS dysfunction.
  • the free base and salt compounds of the present invention modulate the ⁇ 7 NNR subtype, characteristic of the CNS, and can be used for preventing or treating various conditions or disorders, including those of the CNS, in subjects which have or are susceptible to such conditions or disorders, by modulation of the ⁇ 7 NNR.
  • the compounds have the ability to selectively bind to the ⁇ 7 NNR and express nicotinic pharmacology.
  • compounds of the present invention when administered in effective amounts to patients in need thereof, provide some degree of prevention of the progression of the CNS disorder, namely, providing protective effects, amelioration of the symptoms of the CNS disorder, or amelioration of the reoccurrence of the CNS disorder, or a combination thereof.
  • the compounds of the present invention can be used to treat or prevent those types of conditions and disorders for which other types of nicotinic compounds have been proposed or are shown to be useful as therapeutics. See, for example, the references previously listed hereinabove, as well as Williams et al., Drug News Perspec. 7(4): 205 (1994), Arneric et al., CNS Drug Rev. 1(1): 1-26 (1995), Arneric et al., Exp. Opin. Invest. Drugs 5(1): 79-100 (1996), Bencherif et al., J. Pharmacol. Exp. Ther. 279: 1413 (1996), Lippiello et al., J. Pharmacol. Exp. Ther.
  • the compounds and their pharmaceutical compositions are useful in the treatment or prevention of a variety of CNS disorders, including cognitive deficits and dysfunctions, age-related and otherwise and attentional disorders and, in particular schizophrenia.
  • schizophrenia can be divided into three major phases: the prodromal state, an active phase, and a residual phase. These phases tend to occur in sequence and appear in cycles throughout the course of the illness.
  • the residual phase is similar to the prodromal phase although during the residual phase blunted affect and impairment in role functioning are more common.
  • psychotic symptoms may persist into the residual phase, the psychotic symptoms are less likely to be accompanied by such strong affect as experienced during the active phase.
  • After an active phase people may be listless, have trouble concentrating and be withdrawn.
  • the symptoms in this phase are similar to those outlined under the prodromal phase.
  • the treatment or prevention of diseases, disorders, and conditions occurs without appreciable adverse side effects, including, for example, significant increases in blood pressure and heart rate, significant negative effects upon the gastro-intestinal tract, and significant effects upon skeletal muscle.
  • the compounds of the present invention when employed in effective amounts, are believed to modulate the activity of the ⁇ 7 NNR without appreciable interaction with the nicotinic subtypes that characterize the human ganglia, as demonstrated by a lack of the ability to elicit nicotinic function in adrenal chromaffin tissue, or skeletal muscle, further demonstrated by a lack of the ability to elicit nicotinic function in cell preparations expressing muscle-type nicotinic receptors.
  • these compounds are believed capable of treating or preventing diseases, disorders, and conditions without eliciting significant side effects associated activity at ganglionic and neuromuscular sites.
  • administration of the compounds is believed to provide a therapeutic window in which treatment of certain diseases, disorders, and conditions is provided, and certain side effects are avoided. That is, an effective dose of the compound is believed sufficient to provide the desired effects upon the disease, disorder, or condition, but is believed insufficient, namely is not at a high enough level, to provide undesirable side effects.
  • the present invention provides the use of a compound of the present invention, or a pharmaceutically acceptable salt thereof, for use in therapy, such as a therapy described above.
  • the precipitated salt was collected by suction filtration and recrystallized from 5 mL of methanol. Air drying left 1.4 g of white solid, which was partitioned between chloroform (5 mL) and 2 M sodium hydroxide (5 mL). The chloroform layer and a 5 mL chloroform extract of the aqueous layer were combined, dried (anhydrous sodium sulfate) and concentrated to give a colorless oil (0.434 g). The enantiomeric purity of this free base was determined by conversion of a portion into its N-(tert-butoxycarbonyl)-L-prolinamide, which was then analyzed for diastereomeric purity (98%) using LCMS.
  • the mother liquor from the initial crystallization was made basic ( ⁇ pH 11) with 2 M sodium hydroxide and extracted twice with chloroform (10 mL). The chloroform extracts were dried (anhydrous sodium sulfate) and concentrated to give an oil.
  • Diphenylchlorophosphate (0.35 mL, 0.46 g, 1.7 mmol) was added drop-wise to a solution of benzofuran-2-carboxylic acid (0.28 g, 1.7 mmol) and triethylamine (0.24 mL, 0.17 g, 1.7 mmol) in dry dichloromethane (5 mL).
  • Diphenylchlorophosphate (96 ⁇ L, 124 mg, 0.46 mmol) was added drop-wise to a solution of the benzofuran-2-carboxylic acid (75 mg, 0.46 mmol) and triethylamine (64 ⁇ L, 46 mg, 0.46 mmol) in dry dichloromethane (1 mL).
  • the biphasic mixture was separated, and the organic layer and a chloroform extract (2 mL) of the aqueous layer was concentrated by rotary evaporation.
  • the residue was dissolved in methanol and purified by HPLC on a C18 silica gel column, using an acetonitrile/water gradient, containing 0.05% trifluoroacetic acid, as eluent. Concentration of selected fractions, partitioning of the resulting residue between chloroform and saturated aqueous sodium bicarbonate, and evaporation of the chloroform gave 82.5 mg (50% yield) of a white powder.
  • the NMR spectrum was identical to that obtained for the 2S,3R isomer.
  • trans enantiomer B Since the immediate precursor of this material (trans enantiomer B) is enantiomeric to the immediate precursor of 2S,3R compound (trans enantiomer A), the absolute configuration of trans enantiomer B is presumed to be 2R,3S.
  • 3-Quinuclidinone hydrochloride (8.25 kg, 51.0 mol) and methanol (49.5 L) were added to a 100 L glass reaction flask, under an nitrogen atmosphere, equipped with a mechanical stirrer, temperature probe, and condenser.
  • Potassium hydroxide (5.55 kg, 99.0 mol) was added via a powder funnel over an approximately 30 min period, resulting in a rise in reaction temperature from 50° C. to 56° C.
  • 3-pyridinecarboxaldehyde (4.80 kg, 44.9 mol) was added to the reaction mixture.
  • the resulting mixture was stirred at 20° C. ⁇ 5° C. for a minimum of 12 h, as the reaction was monitored by thin layer chromatography (TLC).
  • reaction mixture was filtered through a sintered glass funnel and the filter cake was washed with methanol (74.2 L).
  • the filtrate was concentrated, transferred to a reaction flask, and water (66.0 L) was added.
  • the suspension was stirred for a minimum of 30 min, filtered, and the filter cake was washed with water (90.0 L) until the pH of the rinse was 7-9.
  • the solid was dried under vacuum at 50° C. ⁇ 5° C. for a minimum of 12 h to give 8.58 kg (89.3%) of 2-((3-pyridinyl)methylene)-1-azabicyclo[2.2.2]octan-3-one.
  • the evacuation and pressurization with hydrogen were repeated 2 more times, leaving the reactor under 20 inches water pressure of hydrogen gas after the third pressurization.
  • the reaction mixture was stirred at 20° C. ⁇ 5° C. for a minimum of 12 h, and the reaction was monitored via TLC.
  • the suspension was filtered through a bed of Celite®545 (1.9 kg) on a sintered glass funnel, and the filter cake was washed with methanol (10.1 L).
  • the filtrate was concentrated to obtain a semi-solid which was transferred, under an nitrogen atmosphere, to a 200 L reaction flask fitted with a mechanical stirrer, condenser, and temperature probe.
  • the semi-solid was dissolved in ethanol (57.2 L), and di-p-toluoyl-D-tartaric acid (DTTA) (9.74 kg, 25.2 mol) was added.
  • DTTA di-p-toluoyl-D-tartaric acid
  • the stirring reaction mixture was heated at reflux for a minimum of 1 h, and for an additional minimum of 12 h while the reaction was cooled to between 15° C. and 30° C.
  • the suspension was filtered using a tabletop filter, and the filter cake was washed with ethanol (11.4 L).
  • Dichloromethane (34.7 L) was added to the remaining aqueous phase, and the suspension was stirred for between 2 min and 10 min. The layers were allowed to separate for between 2 min and 10 min. Again, the organic phase was removed and dried over anhydrous sodium sulfate. The extraction of the aqueous phase with dichloromethane (34.7 L) was repeated one more time, as above. Samples of each extraction were submitted for chiral HPLC analysis. The sodium sulfate was removed by filtration, and the filtrates were concentrated to obtain (2S)-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octan-3-one (4.0 kg) as a solid.
  • reaction mixture was cooled to below ⁇ 5° C., and sodium borohydride (1.53 kg, 40.5 mol) was added in portions, keeping the reaction temperature below 15° C. (this addition took several hours).
  • the reaction mixture was then stirred at 15° C. ⁇ 10° C. for a minimum of 1 h.
  • the reaction was monitored by HPLC, and upon completion of the reaction (as indicated by less than 0.5% of (2S)-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octan-3-one remaining), 2 M sodium hydroxide (15.99 L) was added and the mixture was stirred for a minimum of 10 min.
  • the reaction mixture was filtered through a bed of Celite®545 in a tabletop funnel. The filter cake was washed with ethanol (15.23 L), and the filtrate was concentrated to obtain an oil.
  • the concentrate was transferred to a clean 100 L glass reaction flask equipped with a mechanical stirrer and temperature probe under an inert atmosphere. Water (1 L) was added, and the mixture was cooled to 0° C. ⁇ 5° C. 2 M Hydrochloric acid (24 L) was added to the mixture to adjust the pH of the mixture to pH 1. The mixture was then stirred for a minimum of 10 min, and 2 M sodium hydroxide (24 L) was slowly added to adjust the pH of the mixture to pH 14. The mixture was stirred for a minimum of 10 min, and the aqueous phase was extracted with dichloromethane (3 ⁇ 15.23 L).
  • the filter cake was transferred to a clean 100 L glass reaction flask equipped with a mechanical stirrer, temperature probe, and condenser under an inert atmosphere.
  • a 9:1 ethanol/water solution (30.7 L) was added, and the resulting slurry was heated at gentle reflux for a minimum of 1 h.
  • the reaction mixture was then stirred for a minimum of 12 h while cooling to between 15° C. and 30° C.
  • the mixture was filtered and the filter cake was washed with ethanol (5.76 L).
  • the product was collected and dried under vacuum at 50° C. ⁇ 5° C.
  • a hydrochloric acid/THF solution was prepared by adding of concentrated hydrochloric acid (1.93 mL of 12M, 23.2 mmol) drop-wise to 8.5 mL of chilled THF.
  • (2S,3R)—N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide or pharmaceutically acceptable salt thereof met the protocol criteria for a positive result on the primary efficacy outcome measure, the Groton Maze Learning Task (GMLT) of the CogState Schizophrenia Battery (CogState, New Haven, Conn.; http://www.cogstate.com/go/clinicaltrials/our-test-batteries/schizophrenia-battery), and was well tolerated.
  • GMLT Groton Maze Learning Task
  • CogState is a provider of cognitive testing products and services that predominantly caters to the global pharmaceutical industry.
  • the Schizophrenia Cognitive Test Battery covers all domains identified by MATRICS initiative; requires around 35 minutes for administration; is sensitive to the effects of novel compounds and licensed medication; is sensitive to the effects of medication in groups or individual patients; and the outcome measures are related to functional status.
  • FIG. 2 illustrates sensitivity of the primary outcome measures from the CogState schizophrenia battery to cognitive impairment in patients with chronic schizophrenia who were receiving antipsychotic medication in three different geographical areas. The nature and magnitude of impairment in the different cognitive domains was consistent across the three cultural groups.
  • the test battery is rapid. It covers all necessary domains in around 35 minutes—a benefit when working with patients suffering from schizophrenia.
  • the user-friendly test battery allows for non-expert administration on standard computer equipment, which reduces costs and increases efficiency.
  • the tasks utilize culture-neutral stimuli, which ensures that they can be integrated into clinical trials all around the world regardless of culture, ethnicity and socio-economic status.
  • the test battery has high test-retest reliability, which ensures quality data.
  • the pre-task on-screen instructions ask: “Has the card Processing/Simple turned over?” A playing card is presented in the center Reaction Time of the screen. The card will flip over so it is face up. As soon as it does, the subject must press the “Yes” key. The card will go to the back of the pack and the subject must press the “Yes” key as soon as the next card flips over and so on. Attention/Vigilance Identification
  • the pre-task on-screen instructions ask: “Is the card red?” A playing card is presented in the center of the screen. The card will flip over so it is face up. As soon as it does this the subject must decide whether the card is red or not.
  • the pre-task on-screen instructions ask: “Does the face up card exactly match the one before?” A playing card is presented face up in the center of the screen. The subject must decide as each card is presented whether it is identical to the one just before. If the card is identical to the card presented immediately before it, they should press “Yes” if it is not they should press “No”. Visual Learning One Card Learning The pre-task on-screen instructions ask: “Have you seen this card before in this task?” A playing card is presented in the center of the screen. As soon as it does the subject must decide whether or not the same card has been seen before in this task.
  • Subjects must try to remember all the cards that have been shown previously in order to decide whether or not they have seen each card before.
  • Verbal Learning International The subject is told by the test supervisor: “In this task, Shopping List I am going to read you a shopping list. I would like you to remember as many items from this list as possible. Are you ready to start?”
  • the test supervisor reads the list of words as they appear on the computer screen. When the test supervisor has read all the words, the subject is required to recall as many items as possible from the list.
  • Reasoning/Problem Groton Maze The subject is shown a 10 ⁇ 10 grid of tiles on a Solving Learning computer touch screen. A 28-step pathway is hidden among these 100 possible locations.
  • the start is indicated by a blue tile at the top left and the finish location is a tile with the red circles at the bottom right of the grid.
  • the subject is instructed to move one step from the start location and then to continue, one tile at a time, toward the end (bottom right).
  • Social Cognition Social-Emotional
  • the pre-task on-screen instructions ask, “Tap the odd Cognition one out”. In this task, the subject will see a number of pictures on the screen. One of these pictures will be different to the others in some way. The subject must decide which one of the pictures is different, then tap that picture as quickly as they can.
  • the GMLT is a computerized test designed to assess executive function (the ability to organize cognitive processes, including the ability to plan, prioritize, stop and start activities, shift from one activity to another activity and to monitor one's own behavior). Impaired executive function is thought to be an important aspect of cognitive dysfunction in schizophrenia.
  • the trial protocol (see hereinafter—the Protocol) defined a positive outcome on GMLT as superiority (one-sided p-value ⁇ 0.10) for the (2S,3R)—N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide pharmaceutically acceptable salt dose group as compared to the placebo dose group after adjusting statistically to account for 3 multiple comparisons (at Weeks 4, 8, and 12 to evaluate the 3 doses).
  • CogState objective cognitive endpoints including but not limited to composite score, detection (psychomotor speed), identification (attention), 1-card learning (visual learning), 1-back (working memory), and International Shopping List (verbal learning), provided statistically significant results of improvement.
  • Table 2 provides the results of primary, secondary, and CogState analyses of the total population (tobacco users and non-users).
  • Table 3 provides the results of primary, secondary, and CogState analyses in tobacco users.
  • (2S,3R)—N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof exhibited a favorable tolerability profile in the trial, and there was no clinically significant difference between the (2S,3R)—N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof and placebo dose groups in discontinuations due to adverse events.
  • (2S,3R)—N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide pharmaceutically acceptable salt may have acted upon sensitized alpha7 NNRs due to a night-time deprivation of nicotinic stimulation. Whether any of these or other factors underlie the greater effect of (2S,3R)—N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof in tobacco users in this study will require further preclinical and clinical research.
  • One aspect of the invention includes a combination of (2S,3R)—N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide or a pharmaceutically acceptable salt thereof.

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